Gibberellins (including gibberellins A3 and A7) used in ulcer or wound healing

Abstract

Compounds of formula (1), (Gibberellins), and their pharmaceutically acceptable derivatives to promote ulcer-healing, healing of surgical wounds or open fractures and treatment of bronchitis or thrombophlebitis in animals including humans or cultivation of skin cell lines in vitro ##STR1## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20 alkyl, allyl, aryl, arylalkyl, amidine, NR 4 R 5 or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4 and R 5 may or may not be the same, are hydrogen, or C 1-20 alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen and sulfur; B is hydrogen, hydroxyl, mercaptan, or halogen, or A and B together form a --CO--O-- linkage; R 1 is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4 R 5 , unsubstituted or substituted C 1-20 alkyl, allyl, aryl, arylalkyl, and R 2 is methylene, or a divalent hetero-atom.

What is claimed is: 
     
       1. A method of treatment comprising adhibiting compounds of formula (1), (Gibberellins), and their pharmaceutically acceptable derivatives in the absence of added lysine as an active agent, to promote ulcer-healing, healing of open fractures and treatment of bronchitis or thrombophlebitis in animals including humans or cultivation of skin cell lines in vitro. ##STR3## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may be the same or different, and represent hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom.   
     
     
       2. The method of claim 1, wherein the Gibberellins are Gibberellin A 3  so that A--B is --CO--O--, R 1  is hydroxyl and R 2  is methylene. 
     
     
       3. The method of claim 1, wherein the Gibberellins are a mixture of Gibberellin A 3  and Gibberellin A 7 . 
     
     
       4. The method of claim 1, wherein the pharmaceutically acceptable derivatives are salts, including alkali metal salts, alkaline earth metal salts, and salts of ammonium, organic bases, procaine, or lidocaine. 
     
     
       5. The method of claim 4, wherein the organic base is NR 6  R 7  R 8  R 9 , where R 6 , R 7 , R 8  and R 9  may be the same or different and are C 1-20  alkyl, alkanol or aryl. 
     
     
       6. A method of promoting ulcer-healing, comprising administering an effective amount of a compound of formula (1) (Gibberellins) ##STR4## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom, to a patient in need thereof.   
     
     
       7. A method according to claim 6, wherein the Gibberellins are Gibberellin A 3 . 
     
     
       8. A method according to claim 6, wherein the Gibberellins are a mixture of Gibberellin A 3  and Gibberellin A 7 . 
     
     
       9. The method of claim 6, when used in the treatment of leg ulcer, peptic ulcer, aphthous ulcer or decubitus ulcer. 
     
     
       10. A method of treating bronchitis or thrombophlebitis comprising administering an effective amount of a compound of formula (1) (Gibberellins) ##STR5## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom, to a patient in need thereof.   
     
     
       11. A method according to claim 10, wherein the Gibberellins are Gibberellin A 3 . 
     
     
       12. A method according to claim 11, wherein the Gibberellins are a mixture of Gibberellin A 3  and Gibberellin A 7 . 
     
     
       13. A method of promoting healing of open fractures comprising administering an effective amount of a compound of formula (1) (Gibberellin) ##STR6## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom, to a patient in need thereof.   
     
     
       14. A method according to claim 13, wherein the Gibberellins are Gibberellin A 3  and A 7 . 
     
     
       15. A method according to claim 13, wherein the Gibberellins are a mixture of Gibberellins A 3  and Gibberellin A 7 . 
     
     
       16. A method of promoting cultivation of skin cell lines in vitro including providing an effective amount of a compound of formula (1) (Gibberellin) ##STR7## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom, to a skin cell line culture.   
     
     
       17. A method according to claim 16, when used in the promotion of cultivation of skin cell lines for plastic surgery. 
     
     
       18. A method according to claim 16, wherein the Gibberellins are Gibberellin A 3  and A 7 . 
     
     
       19. A method according to claim 16, wherein the Gibberellins are a mixture of Gibberellin A 3  and Gibberellin A 7 . 
     
     
       20. A pharmaceutical composition comprising a compound of formula (1), as an active ingredient, ##STR8## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  which may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, and   R 2  is methylene, or a divalent hetero-atoms; a further active ingredient selected from urea, antibiotics, antiseptic agents, vitamins, β-1,3-glucan, medicinal herbs or mixtures thereof and a pharmaceutically acceptable carrier.     
     
     
       21. A pharmaceutical composition according to claim 20, wherein the carrier is selected from sucrose, acacia, tragicanth, gelatin, glycerin, cocoa butter, propylene glycol, polyethylene glycols, benzolkamium chloride, polysorbates, buffers, isotonicity-adjusting agents, absorption enhancers, viscosity enhancers, suspending agents, surfactants, lactose, starch or starch derivatives and mixtures thereof. 
     
     
       22. A method of manufacturing a composition according to claim 20, comprising combining a compound of formula (1) ##STR9## wherein A is COOR, where R is hydrogen, unsubstituted or substituted C 1-20  alkyl, allyl, aryl, arylalkyl, amidine, NR 4  R 5  or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; R 4  and R 5  may or may not be the same, are hydrogen, or C 1-20  alkyl, allyl, aryl, arylalkyl or an unsaturated or saturated ring containing one or more hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; B is hydrogen, hydroxyl, mercaptan, or halogen,   or A and B together form a --CO--O-- linkage,   R 1  is hydrogen, hydroxyl, mercaptan, halogen, amino, azido, NR 4  R 5 , unsubstituted or substituted C 1-20  alkyl, allyl, aryl, or arylalkyl, and   R 2  is methylene, or a divalent hetero-atom; and a further active ingredient selected from urea, antibiotics, antiseptic agents, vitamins, β-1,3-glucan, medicinal herbs or mixtures thereof, with a pharmaceutically acceptable carrier.